Nu-(beta-pyrrolidinoethyl)-phenothiazine



Patented Oct. 4, 1949 UNITED STATES PATENT OFFICE N-(BETA-PYRROLIDINOETHYL) PHENOTHIAZINE James H. Hunter and WilliamBradley Reid, Jr., Kalamazoo, Mich., assignors to The Up olm Company,Kalamazoo, Mich., a corporation of Michigan No Drawing. ApplicationSeptember 15, 1947, Serial No. 774,178

7 Claims.

The present invention relates to a new chemical compound, N- (betapyrrolidinoethyD- phenothiazine, represented by the formula:

free base, which is a high-boiling liquid, soluble in' organic solventsand slightly soluble in waters;

or as salts thereof, usually high-melting solids, many of which aresoluble in water N (beta pyrrolzdmoethyl) phenothiazine It is an objectof the present invention to pro- O a h d u pension of 4.29 grams (0.11vide a novel compound, N-(beta-pyrrolidino-' mole) of sodium amide in100 milliliters of dry ethyl) -phenothiazine, and salts thereof, whichtoluene was added 19.9 rams (0.1 mole) of materials are usefultherapeutically. Other chphenothiazine. The solution was heated atrejects of the invention will become apparent hereflux for two hours.the s di alt of phenoinafter. thiazine precipitating from solution. Thetol- The free base of the present invention forms Ilene Suspension ofthe Sodium Salt of p n stable salts t id such as hydrochloric, 1-thiazine was cooled to room temperature, wherefurlc, acetic, oxalic,tartaric, citric, et cetera, as 5 upon there was added r pwlse withcontinued well as the methobromide, ethochloride, ethyl Stirring 13.36grams (0.1 mole) of beta-py olipara-toluenesulfonat and other quaternaryamdinoethyl chloride in 50 milliliters of dry toluene. monium salts. Theacid addition salts are pre- After addition was complete, he solutionwas pared from the free base by reaction with the heated under reflux. wh irrin for an addidesired acid, while the quaternary ammonium 3o tional15 hoursp o l n the toluene was salts are prepared by reaction of thefree base extracted withdilute ydrochloric acid and the with a selectedalkyl halide or aryl or alkyl suloluene th n dl carded- The aqueous acidsolufonic ester, all as previously known in the art. tiOn was madealkaline Wlth dilute Sodium y- The pharmacology of the compounds of thisind xide, the crude N-(beta-pyrrolldmoe hyhvention has been studied andthe results ob- Phenflthiazme p ra i as a brownish oil. tained from useof the compounds as antihis- The oil was extracted with ether, the ethertaminics have been described in articles by Samsolution dried withanhydrous magnesium suluel M. Feinberg, Bengt Noren and Robert H. fate.a d t n fi ter d- Dry hydrogen chloride Feinberg, in Journal of Allergy,March 1948, vol. was passed into the ether solution and a semi- 19,pages 90 to 99, and Milton J. Vander Brook, Solid aswhich crystallizedafter scratching, Kenneth J. Olson, Marilyn T. Richmond and separatedtherefrom. The crude N-(beta- Marvin H. Kuizenga, in The Journal ofPharpyrr lidinoethyli-phenothiazine was separated macology andExperimental Therapeutics, Octofrom the ether and. after w y liz ti n-sber, 1948, vol. 94, No. 2, pages 197 to 208. from isopropanol, 17.0grams of desired product,

The new compounds may be obtained by remelting at 196-197 degreescentigrade (uncorn),

action of a beta-pyrrolidinoethyl halide, e. g., the chloride, withphenothiazine in the presence of an alkaline condensing agent, e. g.,sodium, potassium, sodium amide, a lithium amide, sodium hydride,potassium carbonate, et cetera. The hydrogen on the phenothiazinenucleus is replaced by the alkali metal, giving the alkali metal salt,which then reacts with the alkyl halide (prepared irom the halidehydrohalide by known procedure), to yield the N-(beta-pyrrolidinoethyl)-phenothiazine. The free base may be separated as such, or converted toa desired salt as previously disclosed. In some instances, thebeta-pyrrolidinoethyl halide hydrohallde may be advantageously employeddirectly in the process.

Beta-pyrrolidinoethyl halide hydrohalides may be prepared frombeta-pyrrolidinoethanolby treatment with thionyl chloride or bromide,the alcohol being prepared from ethylene oxide and pyrrolidine,according to known procedure for the condensation of alkylene oxides.

The following example is given to illustrate the practice of the presentinvention, but is not to be construed as limiting.

was obtained.

Reference is made to my copending application Serial 774,177, filedconcurrently herewith, in which homologues of the compounds of thisinvention are described and claimed.

Various modifications may be made in the invention without departingfrom the spirit or scope thereof, and it is to be understood that welimit ourselves only as defined in the appended claims.

3 we claim: 1.An N (beta. pyrrolidinoethyl) phenothiazine derivative ofthe group consisting of (0) compounds represented by the formula:

and (1)) acid addition salts and (c) quaternary ammonium salts of thesaid N-(pyrrolidinoethyl) -phenothiazine.

2. N- (beta-pyrrolidinoethyl) -phenothiazine.

3. An acid addition salt of N-(heta-pyrrolidinoethyl) -phenothiazine.

4. N (beta pyrrolidinoethyl) phenothiazine hydrochloride.

5. A quaternary ammonium salt of N-(betapyrrolidinoethyl)-phenothiazine.

6. N (beta pyrrolidinoethyl) phenothiazine ethochloride.

REFERENCES CITED The following references are of record in the file oi.this patent:

UNITED STATES PATENTS Name Date Djerassi et ai. Aug. 27 19 OTHERREFERENCES Survey of Antimalarial Drugs by Frederick Y. Wiselogle. vol.2, part I. p. 699 (1946).

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